EP0002495A1 - Composition à utiliser en thérapie cytostatique - Google Patents
Composition à utiliser en thérapie cytostatique Download PDFInfo
- Publication number
- EP0002495A1 EP0002495A1 EP78101583A EP78101583A EP0002495A1 EP 0002495 A1 EP0002495 A1 EP 0002495A1 EP 78101583 A EP78101583 A EP 78101583A EP 78101583 A EP78101583 A EP 78101583A EP 0002495 A1 EP0002495 A1 EP 0002495A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- chloroethyl
- oxo
- acid
- cytostatic
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000824 cytostatic agent Substances 0.000 title claims abstract description 46
- 230000001085 cytostatic effect Effects 0.000 title claims abstract description 39
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 229940100198 alkylating agent Drugs 0.000 claims abstract description 16
- 239000002168 alkylating agent Substances 0.000 claims abstract description 16
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 15
- ZNEWHQLOPFWXOF-UHFFFAOYSA-N coenzyme M Chemical compound OS(=O)(=O)CCS ZNEWHQLOPFWXOF-UHFFFAOYSA-N 0.000 claims description 13
- 229960001101 ifosfamide Drugs 0.000 claims description 13
- 229940006193 2-mercaptoethanesulfonic acid Drugs 0.000 claims description 12
- 159000000000 sodium salts Chemical class 0.000 claims description 12
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 11
- 229960004397 cyclophosphamide Drugs 0.000 claims description 8
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 claims description 6
- 229960000875 trofosfamide Drugs 0.000 claims description 6
- ZSZKJARKHWCBJK-UHFFFAOYSA-N 2-[[3-(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-yl]amino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCNP1(=O)OCCCN1CCCl ZSZKJARKHWCBJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- -1 1,2-ethylene Chemical group 0.000 claims description 3
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 5
- 229940127557 pharmaceutical product Drugs 0.000 claims 5
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical compound ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 claims 1
- 210000003932 urinary bladder Anatomy 0.000 abstract description 16
- 150000007513 acids Chemical class 0.000 abstract description 8
- 210000003734 kidney Anatomy 0.000 abstract description 7
- 210000001635 urinary tract Anatomy 0.000 abstract description 7
- 230000007794 irritation Effects 0.000 abstract description 3
- 229910006069 SO3H Inorganic materials 0.000 abstract 1
- 206010000210 abortion Diseases 0.000 abstract 1
- 231100000176 abortion Toxicity 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 18
- 206010028980 Neoplasm Diseases 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 210000002700 urine Anatomy 0.000 description 5
- 201000003146 cystitis Diseases 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 208000006750 hematuria Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- 229960004308 acetylcysteine Drugs 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001784 detoxification Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- COSZWAUYIUYQBS-UHFFFAOYSA-B hexapotassium hexasodium 3-carboxy-3-hydroxypentanedioate 2-hydroxypropane-1,2,3-tricarboxylate hydrate Chemical compound O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[K+].[K+].[K+].[K+].[K+].[K+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O COSZWAUYIUYQBS-UHFFFAOYSA-B 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000002633 shock therapy Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229950008275 sufosfamide Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- ZZVDXRCAGGQFAK-UHFFFAOYSA-N 2h-oxazaphosphinine Chemical class N1OC=CC=P1 ZZVDXRCAGGQFAK-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- MRIMWDXKBILRPB-UHFFFAOYSA-N O=P1NCCCO1 Chemical class O=P1NCCCO1 MRIMWDXKBILRPB-UHFFFAOYSA-N 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000005584 early death Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000021962 pH elevation Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Definitions
- alkylantia cytostatics such as melphalan, cyclophosphamide, trofosfamide, ifosfamide, sufosfamide, chlorambucil, busulfan, triethylene thiophosphamide or triaziquone and in particular the 2-oxo-1,3,2-oxazaphosphorinanes cyclophosphamide, trofosfamide, ifosfanide and severe side effects occur as undesirable effects Irritation of the kidney, urinary tract and / or the bladder of the treated patient. It is known that these side effects occur particularly easily after the first damage. This undesirable side effect can be so severe that the therapy of the patient suffering from cancer is temporarily interrupted or even completely impossible.
- cytostatics are administered when they are first applied in a single dose that is high in relation to their toxicity in order to achieve the highest possible initial concentration of the cytostatic in the tumor tissue. Thereafter, the cytostatics are often administered in lower doses over long periods of time. It is known that the undesirable side effect described is caused by metabolites of cytostatics formed in the patient's body.
- the side effect occurs with alkylants known for some time, such as those known under the well-known name Endoxan® or cyclophosphamide 2- (N, N-bis- (2-chloroethyl) -amino) -2-oxo-1,3,2-oxazaphosphorinane and under the 2- (N, N-bis- known as IxotenQ9 or trofosfamide (2-chloroethyl) amino) -3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane frequently.
- This side effect is even more important if you administer highly cytostatic and at the same time less toxic alkylating agent cytostatics such as ifosfamide.
- the therapeutic uses which are due to the low toxicity, are significantly limited by this side effect. It has even been observed that bladder cancer developed due to such irritation of the bladder.
- This so-called hydration is generally associated with an alkalinization of the urine, for example with the hexakalium hexasodium pentacitrate hydrate complex commercially available under the name Uralyt® -U, and in particular with the introduction of solutions of compounds containing mercapto groups into the bladder through catheters.
- Such compounds containing mercapto groups were thought to react with the alkylating groups and so on deactivated.
- N-acetylcysteine and cysteine were used as such a compound.
- success has been limited, particularly when using cytostatics in very high doses.
- bladder irrigation is difficult for the patient and practically hardly feasible when the cytostatics are administered over long periods of time. After all, higher areas of the urinary tract are not accessible at all.
- the salt of mercaptoalkanesulfonic acid can be administered in the same or in a different usual application form than the cytostatic agent.
- the cytostatic can be administered intravenously, while the salt of mercaptoalkanesulfonic acid can be administered orally or intraperitoneally.
- the salt of mercaptoalkanesulfonic acid is preferably administered simultaneously with the cytostatic agent. This applies in particular to the high initial dose customary in shock therapy. Both compounds are then preferably administered in a single application unit.
- the present invention thus relates to the use of pharmacologically acceptable salts of a mercaptoalkanesulfonic acid of the general formula wherein alk is a straight-chain or branched alkylene radical having 2 to 6 carbon atoms, in cytostatic therapy with alkylating agents, be it in the form of combination preparations containing the salt and the alkylan, or in the form of separate preparations for the simultaneous or time-graded combined administration of certain preparations .
- the alkali salts are very particularly suitable here, especially the sodium salt of 2-mercaptoethanesulfonic acid.
- the administration of amounts as small as 20% of the dose of the cytostatic is sufficient. This is especially true at lower doses of the cytostatic. At higher doses of the cytostatic, the harmful side effect can be prevented with 30% of the amount of the cytostatic. Since the side effect is particularly important when administering the cytostatics in high doses, the lower limit of 30% of the amount of the cytostatic is preferably used. In view of the known, very low toxicity of the pharmacologically acceptable salts of mercaptoalkanesulfonic acids, the upper limit of the quantity range for the salt of mercaptoalkanesulfonic acid is of minor importance.
- cytostatic activity of the alkylating agents is not impaired. In animal experiments, this was found for ifosfamide even with a 100-fold greater dose of the sodium salt of beta-mercaptoethanesulfonic acid than the dose of the cytostatic. Since a practical elimination of the side effect is generally achieved even with high doses of cytostatics with equal amounts of the salt of mercaptoalkanesulfonic acid, it is preferred to add the salt of mercaptoalkanesulfonic acid in an amount corresponding to 30 to 100% of the amount when the mercaptoalkanesulfonic acid is administered prior to administration Apply cytostatic to be administered or the administered cytostatic.
- salts of mercaptoalkanesulfonic acids can be used in conjunction with all alkylating agents and thereby prevent the described harmful and particularly undesirable side effect, they have particular their importance in connection with the 2-0xo-1,3,2-oxazaphosphorinane cyclophosphamide, ifosfamide, trofosfamide and sufosfamide used to a large extent to combat a wide variety of cancers.
- mercaptoalkanesulfonic acids used according to the invention are known compounds (cf. US Pat. No. 2,694,732). They have also been used for therapeutic purposes, specifically as mucolytically active compounds in preparations other than those required for the use according to the invention (cf. DE-OS 1 620 629). However, these or similar compounds have so far not been used to prevent the side effect of the alkylating agent cytostatics described.
- a 56-year-old patient suffering from kidney hypernephroma is treated according to the rules of therapy, with radiation and ifosfamide [2- (N-2-chloroethylamino) -3- (2-chloroethyl) -2-oxo- 1,3,2-oxazaphosphorinan] (5 x 60 mg / kg intravenously for 5 consecutive days).
- the patient is hydrated by adding 4 liters of water throughout the day and alkalized by administration of hexapotassium hexasodium pentacitrate-hydrate complex.
- the patient reacts with strong macrohematuria, which forces the therapy to be stopped immediately.
- the therapy is repeated, but this time, with each dose of 60 mg / kg ifosfamide, 35 mg / kg of the sodium salt of 2-mercaptoethanesulfonic acid is administered intravenously.
- the patient was checked daily for micro and macro hematuria or protein excretion in the urine. There were no signs of hematuria or protein excretion.
- the sodium salt of 2-mercapto-ethanesulfonic acid was administered orally 1/2 hour before application of the alkylane.
- a dosage of 30 mg / kg to 60 mg / kg of the sodium salt of 2-mercaptoethanesulfonic acid at a dose of 60 mg / kg of the alkylane no harmful side effects were demonstrated.
- the effectiveness of the salts of mercaptoalkanesulfonic acids of the general formula described above was investigated on the model of ifosfamide cystitis in the rat.
- a single intravenous dose of 68.1 mg / kg ifosfamide or cyclophosphamide can cause cystitis in the rat.
- a trypan blue solution is administered intravenously to the animals 24 hours after the cytostatic agent has been administered, and the animals are sacrificed under ether anesthesia after a further 30 minutes. With the help of the vital dye trypan blue, foci of inflammation can be displayed macroscopically.
- the bladders of the test animals are deep blue in color, swollen and some have bleeding.
- the investigated compounds used according to the invention were administered simultaneously with the cytostatic agent or up to 15 min before application of the cytostatic agent i.v. administered.
- the toxicity of the investigated compounds was approximately the same and very low (DL 50> 2000 mg / kg).
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Toxicology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2756018 | 1977-12-14 | ||
| DE2756018A DE2756018C2 (de) | 1977-12-14 | 1977-12-14 | Verwendung von Salzen von Mercaptoalkansulfonsäuren |
| DE2827625 | 1978-06-23 | ||
| DE2827625 | 1978-06-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0002495A1 true EP0002495A1 (fr) | 1979-06-27 |
| EP0002495B1 EP0002495B1 (fr) | 1984-02-15 |
Family
ID=25773277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78101583A Expired EP0002495B1 (fr) | 1977-12-14 | 1978-12-06 | Composition à utiliser en thérapie cytostatique |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4220660A (fr) |
| EP (1) | EP0002495B1 (fr) |
| JP (1) | JPS54101432A (fr) |
| DK (1) | DK154608C (fr) |
| FI (1) | FI783756A (fr) |
| NO (1) | NO784192L (fr) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0198542A1 (fr) * | 1985-04-15 | 1986-10-22 | Schering Spa | Compositions pharmaceutiques à base d'acide mercaptoéthanesulfonique, dérivés salins organiques d'acide mercaptoéthanesulfonique et leur procédé de fabrication |
| US4716242A (en) * | 1984-03-01 | 1987-12-29 | Asta-Werke Aktiengesellschaft Chemische Fabrik | Salts of oxazaphosphorine derivatives |
| EP0334083A1 (fr) * | 1988-03-19 | 1989-09-27 | ASTA Pharma Aktiengesellschaft | Composition lyophilisée à base de ifosfamide-mesna et procédé pour sa préparation |
| US5663145A (en) * | 1993-12-09 | 1997-09-02 | Asta Medica Aktiengesellschaft | Products for administering an initial high dose of Cetrorelix and producing a combination package for use when treating diseases |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5244920A (en) * | 1985-04-15 | 1993-09-14 | Schering Spa | Pharmaceutical compositions having therapeutical activity based on mercaptoethansulphonic arginine salt |
| JPH01174407U (fr) * | 1988-05-26 | 1989-12-12 | ||
| US6197831B1 (en) * | 1999-02-09 | 2001-03-06 | Bionumerik Pharmaceuticals, Inc. | Method of treating septic shock |
| US6077838A (en) * | 1999-06-08 | 2000-06-20 | Bionumerik Pharmaceuticals, Inc. | Method of treating hangover |
| WO2001049822A2 (fr) * | 1999-12-29 | 2001-07-12 | Sergei Mikhailovich Zenovich | Agents physiologiquement actifs contenant dithioglyols et leur application dans differentes secteurs |
| US6245815B1 (en) * | 2000-04-15 | 2001-06-12 | Bionumerik Pharmaceuticals, Inc. | Method of treating alcoholism and complications resulting therefrom |
| US6291441B1 (en) * | 2000-09-27 | 2001-09-18 | Frederick H. Hausheer | Method of treating inflammatory bowel disorders |
| US6352979B1 (en) * | 2001-08-20 | 2002-03-05 | Lucinda Lizcano | Method of treating snakebite and complications resulting therefrom |
| US20050272698A1 (en) * | 2002-09-05 | 2005-12-08 | Daftary Gautam V | Liquid stable composition of oxazaphosphorine with mesna |
| US7025998B2 (en) | 2003-05-30 | 2006-04-11 | Rotta Research Laboratorium S.P.A. | Phytoestrogens and probiotic for women's health |
| ES2369776T3 (es) * | 2003-10-01 | 2011-12-05 | Baxter International Inc. | Nueva utilización, preparados farmacéuticos y procedimiento para su producción. |
| MXPA06006709A (es) * | 2003-12-17 | 2006-08-31 | Bionumerik Pharmaceuticals Inc | Proceso para sintetizar disulfuros. |
| US20060063742A1 (en) * | 2004-09-21 | 2006-03-23 | Hausheer Frederick H | Method of treatment for or protection against lymphedema |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1620629A1 (de) * | 1965-05-07 | 1969-10-16 | Ucb Sa | Verbindungen mit mucolytischer Aktivitaet und sie enthaltende Mittel und Verfahren zu ihrer Herstellung |
-
1978
- 1978-12-06 EP EP78101583A patent/EP0002495B1/fr not_active Expired
- 1978-12-06 US US05/967,000 patent/US4220660A/en not_active Expired - Lifetime
- 1978-12-07 DK DK553978A patent/DK154608C/da not_active IP Right Cessation
- 1978-12-07 FI FI783756A patent/FI783756A/fi unknown
- 1978-12-13 NO NO784192A patent/NO784192L/no unknown
- 1978-12-13 JP JP15906678A patent/JPS54101432A/ja active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1620629A1 (de) * | 1965-05-07 | 1969-10-16 | Ucb Sa | Verbindungen mit mucolytischer Aktivitaet und sie enthaltende Mittel und Verfahren zu ihrer Herstellung |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4716242A (en) * | 1984-03-01 | 1987-12-29 | Asta-Werke Aktiengesellschaft Chemische Fabrik | Salts of oxazaphosphorine derivatives |
| EP0198542A1 (fr) * | 1985-04-15 | 1986-10-22 | Schering Spa | Compositions pharmaceutiques à base d'acide mercaptoéthanesulfonique, dérivés salins organiques d'acide mercaptoéthanesulfonique et leur procédé de fabrication |
| EP0334083A1 (fr) * | 1988-03-19 | 1989-09-27 | ASTA Pharma Aktiengesellschaft | Composition lyophilisée à base de ifosfamide-mesna et procédé pour sa préparation |
| US5663145A (en) * | 1993-12-09 | 1997-09-02 | Asta Medica Aktiengesellschaft | Products for administering an initial high dose of Cetrorelix and producing a combination package for use when treating diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| DK553978A (da) | 1979-06-15 |
| DK154608C (da) | 1989-05-08 |
| JPS54101432A (en) | 1979-08-10 |
| DK154608B (da) | 1988-12-05 |
| JPS6154006B2 (fr) | 1986-11-20 |
| FI783756A (fi) | 1979-06-15 |
| EP0002495B1 (fr) | 1984-02-15 |
| NO784192L (no) | 1979-06-15 |
| US4220660A (en) | 1980-09-02 |
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